Leukemia
Conditions
Keywords
relapsing chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, Philadelphia chromosome positive chronic myelogenous leukemia
Brief summary
RATIONALE: Imatinib mesylate and interferon alfa may interfere with the growth of the cancer cells. Combining imatinib mesylate with interferon alfa may kill more cancer cells. PURPOSE: Phase II trial to study the effectiveness of combining imatinib mesylate with interferon alfa in treating patients who have chronic myelogenous leukemia.
Detailed description
OBJECTIVES: * Determine the maximum tolerated dose of interferon alfa administered with imatinib mesylate in patients with chronic phase chronic myelogenous leukemia. (Phase I closed to accrual as of 7/9/03.) * Determine the safety and tolerability of this regimen in this patient population. * Determine the complete, major, and minor cytogenetic response rates and complete hematologic response rate in patients after 6 and 12 months of treatment with this regimen. * Determine the molecular response (reverse transcriptase-polymerase chain reaction for bcr-abl) rate in patients who have a complete cytogenetic response after 6 and 12 months of treatment with this regimen. * Determine the pharmacokinetics of this regimen in these patients. OUTLINE: This is a dose-escalation, multicenter study. * Phase I (closed to accrual as of 7/9/03): Patients receive oral imatinib mesylate once daily beginning on day 1 and interferon alfa (IFN-A) subcutaneously once daily or 3 times weekly beginning on day 14. Courses repeat every 35 days for up to 1 year in the absence of disease progression or unacceptable toxicity. After completion of 1 year of therapy, patients may receive additional therapy, provided that the patient is benefiting from imatinib mesylate. IFN-A is discontinued in patients who achieve a molecular remission that is confirmed on 2 successive bone marrow samples. Imatinib mesylate is discontinued in patients who achieve and maintain a molecular remission for 2 years. Sequential dose escalation of IFN-A is followed by sequential dose escalation of imatinib mesylate. Cohorts of 3-6 patients receive escalating doses of IFN-A and then imatinib mesylate until the maximum tolerated dose (MTD) of the combination is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. * Phase II: Patients receive imatinib mesylate and IFN-A as in phase I at the established MTD. Patients are followed for 30 days. PROJECTED ACCRUAL: Approximately 3-15 patients will be accrued for the phase I portion of this study. (Phase I closed to accrual as of 7/9/03.) A total of 40 patients will be accrued for the phase II portion of the study within 3-4 months.
Interventions
BIOLOGICALrecombinant interferon alfa
IFN-α will be given at a dose ranging up to 5 MIU daily via subcutaneous injection.
DRUGimatinib mesylate
Once daily oral administration of STI571 (imatinib mesylate) at a dose of 400 mg or 600mg for 12 months.
Sponsors
National Cancer Institute (NCI)
OHSU Knight Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Cytogenetically confirmed chronic myelogenous leukemia (CML) * Less than 15% blasts in peripheral blood or bone marrow * Less than 30% blasts and promyelocytes in peripheral blood or bone marrow * Less than 20% basophils in blood or bone marrow * Platelet count at least 100,000/mm\^3 * No leukemia beyond bone marrow, blood, liver, or spleen * No chloroma * Phase I (closed to accrual as of 7/9/03): * Philadelphia (Ph) chromosome-positive CML in chronic phase * Phase II: * Newly diagnosed Ph chromosome-positive CML in chronic phase * Initial diagnosis within 6 months of study * No prior therapy for CML except hydroxyurea and/or anagrelide hydrochloride * Phase I (closed to accrual as of 7/9/03) and II: * No identified sibling donors where allogeneic stem cell transplantation is elected as first-line therapy PATIENT CHARACTERISTICS: Age: * 18 and over Performance status: * ECOG 0-2 Life expectancy: * Not specified Hematopoietic: * See Disease Characteristics Hepatic: * Bilirubin no greater than 1.5 times upper limit of normal (ULN) * AST or ALT no greater than 2 times ULN Renal: * Creatinine no greater than 1.5 times ULN Cardiovascular: * No New York Heart Association class III or IV heart disease Other: * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use 2 methods of effective barrier contraception during and for at least 3 months after study participation * No other serious uncontrolled medical condition * No autoimmune disease * No prior noncompliance to medical regimens or potential unreliability * No prior grade 3 or greater non-hematologic toxicity due to prior interferon (phase I \[closed to accrual as of 7/9/03\]) PRIOR CONCURRENT THERAPY: Biologic therapy: * See Disease Characteristics * No prior bone marrow or peripheral blood stem cell transplantation * At least 2 weeks since prior interferon alfa (phase I \[closed to accrual as of 7/9/03\]) Chemotherapy: * See Disease Characteristics * At least 6 weeks since prior busulfan (phase I \[closed to accrual as of 7/9/03\] ) * At least 2 weeks since prior cytarabine (phase I \[closed to accrual as of 7/9/03\]) * No concurrent chemotherapy * Concurrent hydroxyurea allowed during the first 3 months of study Endocrine therapy: * Not specified Radiotherapy: * Not specified Surgery: * Not specified Other: * At least 4 weeks since prior investigational agents other than imatinib mesylate (phase I \[closed to accrual as of 7/9/03\]) * No concurrent grapefruit juice * Concurrent anagrelide hydrochloride allowed during the first 3 months of study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Cytogenetic Response at 6 and 12 Months (Phase II) | At 6 and 12 months during phase II | Cytogenetic response in terms of the percentage of Ph chromosome positive metaphases in bone marrow is defined as follows: Complete\* (0% Ph-positive cells) Partial\* (1-34%) Minor (35-95%) None (96-100%). |
| Minor Cytogenetic Response at 6 and 12 Months (Phase II) | At 6 and 12 months during phase II | — |
| Complete Hematologic Response at 6 and 12 Months (Phase II) | At 6 and 12 months during phase II | — |
| Molecular Response in Patients With Complete Cytogenetic Response at 6 and 12 Months (Phase II) | At 6 and 12 months during phase II | — |
| Treatment-related Toxicity (i.e., Grade 3 or 4 Nonhematologic Toxicity) as Measured by NCI CTCAE v3.0 (Phase I) | 12 Months | 1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death |
| Major Cytogenetic Response After 6 and 12 Months of Treatment. | 6 and 12 months after treatment | Cytogenetic response in terms of the percentage of Ph chromosome positive metaphases in bone marrow is defined as follows: Complete\* (0% Ph-positive cells) Partial\* (1-34%) Minor (35-95%) None (96-100%). \*Major cytogenetic response includes complete and partial cytogenetic response. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Imatinib Mesylate Once daily oral administration of STI571 (imatinib mesylate) at a dose of 400 mg or 600mg for 12 months. | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | Imatinib Mesylate |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 25 |
| serious Total, serious adverse events | 8 / 25 |
Outcome results
Primary
Complete Cytogenetic Response at 6 and 12 Months (Phase II)
Cytogenetic response in terms of the percentage of Ph chromosome positive metaphases in bone marrow is defined as follows: Complete\* (0% Ph-positive cells) Partial\* (1-34%) Minor (35-95%) None (96-100%).
Time frame: At 6 and 12 months during phase II
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib Mesylate | Complete Cytogenetic Response at 6 and 12 Months (Phase II) | 13 Participants |
Primary
Complete Hematologic Response at 6 and 12 Months (Phase II)
Time frame: At 6 and 12 months during phase II
Population: The reason why remaining outcomes can not be reported is due to loss of the study data. Results published 13 years ago were only partial at the time despite having overlapping timeframes with other outcomes. Efforts made since to locate original data to report remaining outcomes were unsuccessful due to early termination and staff turnover.
Primary
Major Cytogenetic Response After 6 and 12 Months of Treatment.
Cytogenetic response in terms of the percentage of Ph chromosome positive metaphases in bone marrow is defined as follows: Complete\* (0% Ph-positive cells) Partial\* (1-34%) Minor (35-95%) None (96-100%). \*Major cytogenetic response includes complete and partial cytogenetic response.
Time frame: 6 and 12 months after treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib Mesylate | Major Cytogenetic Response After 6 and 12 Months of Treatment. | 18 Participants |
Primary
Minor Cytogenetic Response at 6 and 12 Months (Phase II)
Time frame: At 6 and 12 months during phase II
Population: The reason why remaining outcomes can not be reported is due to loss of the study data. Results published 13 years ago were only partial at the time despite having overlapping timeframes with other outcomes. Efforts made since to locate original data to report remaining outcomes were unsuccessful due to early termination and staff turnover.
Primary
Molecular Response in Patients With Complete Cytogenetic Response at 6 and 12 Months (Phase II)
Time frame: At 6 and 12 months during phase II
Population: The reason why remaining outcomes can not be reported is due to loss of the study data. Results published 13 years ago were only partial at the time despite having overlapping timeframes with other outcomes. Efforts made since to locate original data to report remaining outcomes were unsuccessful due to early termination and staff turnover.
Primary
Treatment-related Toxicity (i.e., Grade 3 or 4 Nonhematologic Toxicity) as Measured by NCI CTCAE v3.0 (Phase I)
1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death
Time frame: 12 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib Mesylate | Treatment-related Toxicity (i.e., Grade 3 or 4 Nonhematologic Toxicity) as Measured by NCI CTCAE v3.0 (Phase I) | 8 Participants |